Multiple sphingolipid-metabolizing enzymes modulate influenza virus replication.

The sphingolipid network is sustained principally by the balance of bioactive sphingolipid molecules and their regulation by sphingolipid-metabolizing enzymes. The components in the lipid system display key functions in numerous cellular and disease conditions including virus infections. During the COVID-19 pandemic, there was a fruitful effort to use an inhibitor that blocks the activity of sphingosine kinase (SphK) 2 to cure the devastating disease.

Triggering Degradation of Host Cellular Proteins for Robust Propagation of Influenza Viruses.

Following infection, influenza viruses strive to establish a new host cellular environment optimized for efficient viral replication and propagation. Influenza viruses use or hijack numerous host factors and machinery not only to fulfill their own replication process but also to constantly evade the host's antiviral and immune response. For this purpose, influenza viruses appear to have formulated diverse strategies to manipulate the host proteins or signaling pathways.

Protective versus Pathogenic Type I Interferon Responses during Virus Infections.

Following virus infections, type I interferons are synthesized to induce the expression of antiviral molecules and interfere with virus replication. The importance of early antiviral type I IFN response against virus invasion has been emphasized during COVID-19 as well as in studies on the microbiome. Further, type I IFNs can directly act on various immune cells to enhance protective host immune responses to viral infections.

Analyzing Opposing Interactions Between Sphingosine 1-Phosphate Lyase and Influenza A Virus.

Sphingosine 1-phosphate lyase (SPL) is a critical component of sphingosine 1-phosphate (S1P) metabolism. SPL has been associated with several crucial cellular functions due to its role in S1P metabolism, but its role in viral infections is poorly understood. Studies show that SPL has an antiviral function against influenza A virus (IAV) by interacting with IKKɛ, promoting the type I interferon (IFN) innate immune response to IAV infection.

Chronic LCMV Infection Is Fortified with Versatile Tactics to Suppress Host T Cell Immunity and Establish Viral Persistence.

Ever since the immune regulatory strains of lymphocytic choriomeningitis virus (LCMV), such as Clone 13, were isolated, LCMV infection of mice has served as a valuable model for the mechanistic study of viral immune suppression and virus persistence. The exhaustion of virus-specific T cells was demonstrated during LCMV infection, and the underlying mechanisms have been extensively investigated using LCMV infection in mouse models. In particular, the mechanism for gradual CD8 T cell exhaustion at molecular and transcriptional levels has been investigated.

Influenza A virus NS1 induces degradation of sphingosine 1-phosphate lyase to obstruct the host innate immune response.

The type I interferon (IFN)-mediated innate immune response is one of the central obstacles influenza A virus (IAV) must overcome in order to successfully replicate within the host. We have previously shown that sphingosine 1-phosphate (S1P) lyase (SPL) enhances IKKϵ-mediated type I IFN responses. Here, we demonstrate that the nonstructural protein 1 (NS1) of IAV counteracts the SPL-mediated antiviral response by inducing degradation of SPL.

Chios mastic gum inhibits influenza A virus replication and viral pathogenicity.

Chios mastic gum (CMG), a resin of the mastic tree ( var. chia), has been used to treat multiple disorders caused by gastrointestinal malfunctions and bacterial infections for more than 2500 years. However, little is known about CMG's antiviral activity.

Sphingosine kinase 2 restricts T cell immunopathology but permits viral persistence.

Chronic viral infections are often established by the exploitation of immune-regulatory mechanisms that result in nonfunctional T cell responses. Viruses that establish persistent infections remain a serious threat to human health. Sphingosine kinase 2 (SphK2) generates sphingosine 1-phosphate, which is a molecule known to regulate multiple cellular processes.

Special Issue "Viral Evasion or Suppression of Host Immunity".

Viruses have evolved to survive in hosts, presumably by devising meticulous strategies to elude or suppress host immunity [...

PARP1 Enhances Influenza A Virus Propagation by Facilitating Degradation of Host Type I Interferon Receptor.

Influenza A virus (IAV) utilizes multiple strategies to confront or evade host type I interferon (IFN)-mediated antiviral responses in order to enhance its own propagation within the host. One such strategy is to induce the degradation of type I IFN receptor 1 (IFNAR1) by utilizing viral hemagglutinin (HA). However, the molecular mechanism behind this process is poorly understood.

Emerging Connections of S1P-Metabolizing Enzymes with Host Defense and Immunity During Virus Infections.

The sphingosine 1-phosphate (S1P) metabolic pathway is a dynamic regulator of multiple cellular and disease processes. Identification of the immune regulatory role of the sphingosine analog FTY720 led to the development of the first oral therapy for the treatment of an autoimmune disease, multiple sclerosis. Furthermore, inhibitors of sphingosine kinase (SphK), which mediate S1P synthesis, are being evaluated as a therapeutic option for the treatment of cancer.

Transient inhibition of sphingosine kinases confers protection to influenza A virus infected mice.

Influenza continues to pose a threat to public health by causing illness and mortality in humans. Discovering host factors that regulate influenza virus propagation is vital for the development of novel drugs. We have previously reported that sphingosine kinase (SphK) 1 promotes influenza A virus (IAV) replication in vitro.

Viral dedication to vigorous destruction of interferon receptors.

Interferons (IFNs) exhibit forceful inhibitory activities against numerous viruses by inducing synthesis of anti-viral proteins or promoting immune cell functions, which help eradicate the vicious microbes. Consequently, the degree to which viruses evade or counterattack IFN responses influences viral pathogenicity. Viruses have developed many strategies to interfere with the synthesis of IFNs or IFN receptor signaling pathway.

sNASP inhibits TLR signaling to regulate immune response in sepsis.

Many Toll-like receptors (TLRs) signal through TNF receptor-associated factor 6 (TRAF6) to activate innate immune responses. Here, we show that somatic nuclear autoantigenic sperm protein (sNASP) binds to TRAF6 to prevent TRAF6 autoubiquitination in unstimulated macrophages. Following LPS stimulation, a complex consisting of sNASP, TRAF6, IRAK4, and casein kinase 2 (CK2) is formed.

Casein Kinase 1α Mediates the Degradation of Receptors for Type I and Type II Interferons Caused by Hemagglutinin of Influenza A Virus.

Although influenza A virus (IAV) evades cellular defense systems to effectively propagate in the host, the viral immune-evasive mechanisms are incompletely understood. Our recent data showed that hemagglutinin (HA) of IAV induces degradation of type I IFN receptor 1 (IFNAR1). Here, we demonstrate that IAV HA induces degradation of type II IFN (IFN-γ) receptor 1 (IFNGR1), as well as IFNAR1, via casein kinase 1α (CK1α), resulting in the impairment of cellular responsiveness to both type I and II IFNs.

Sphingosine 1-Phosphate Lyase Enhances the Activation of IKKε To Promote Type I IFN-Mediated Innate Immune Responses to Influenza A Virus Infection.

Sphingosine 1-phosphate (S1P) lyase (SPL) is an intracellular enzyme that mediates the irreversible degradation of the bioactive lipid S1P. We have previously reported that overexpressed SPL displays anti-influenza viral activity; however, the underlying mechanism is incompletely understood. In this study, we demonstrate that SPL functions as a positive regulator of IKKε to propel type I IFN-mediated innate immune responses against viral infection.

Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1.

Unlabelled: Influenza A virus (IAV) employs diverse strategies to circumvent type I interferon (IFN) responses, particularly by inhibiting the synthesis of type I IFNs. However, it is poorly understood if and how IAV regulates the type I IFN receptor (IFNAR)-mediated signaling mode. In this study, we demonstrate that IAV induces the degradation of IFNAR subunit 1 (IFNAR1) to attenuate the type I IFN-induced antiviral signaling pathway.

Lactoferrin acts as an adjuvant during influenza vaccination of neonatal mice.

Health policy precludes neonatal vaccination against influenza. Hence, morbidity and mortality are high under 6 months of age. Lactoferrin may activate diminished numbers of dysfunctional dendritic cells and reverse neonatal vaccine failures.

A ceramide analogue stimulates dendritic cells to promote T cell responses upon virus infections.

The ceramide family of lipids plays important roles in both cell structure and signaling in a diverse array of cell types, including immune cells. However, very little is known regarding how ceramide affects the activation of dendritic cells (DCs) in response to viral infection. In this study, we demonstrate that a synthetic ceramide analog (C8) stimulates DCs to increase the expansion of virus-specific T cells upon virus infection.

Influenza viral manipulation of sphingolipid metabolism and signaling to modulate host defense system.

Viruses attempt to create a distinctive cellular environment to favor viral replication and spread. Recent studies uncovered new functions of the sphingolipid signaling/metabolism during pathogenic virus infections. While sphingolipids such as sphingomyelin and ceramide were reported to influence the entry step of several viruses, sphingolipid-metabolizing enzymes could directly alter viral replication processes.

Sphingosine analog AAL-R promotes activation of LCMV-infected dendritic cells.

Sphingosine analogs display diverse immunoregulatory activities with curative potential in autoimmune diseases and viral infections. Recently, the sphingosine analog AAL-R was shown to increase DC activation upon TLR7 stimulation. Here, we investigated the effect of AAL-R on activation of dendritic cells (DCs) infected by lymphocytic choriomeningitis virus (LCMV).

Sphingosine kinase 1 regulates measles virus replication.

Measles virus (MV) manipulates host factors to facilitate virus replication. Sphingosine kinase (SK) is an enzyme catalyzing the formation of sphingosine 1-phosphate and modulates multiple cellular processes including the host defense system. Here, we determined the role of SK1 in MV replication.

Sphingosine kinase 1 serves as a pro-viral factor by regulating viral RNA synthesis and nuclear export of viral ribonucleoprotein complex upon influenza virus infection.

Influenza continues to pose a threat to humans by causing significant morbidity and mortality. Thus, it is imperative to investigate mechanisms by which influenza virus manipulates the function of host factors and cellular signal pathways. In this study, we demonstrate that influenza virus increases the expression and activation of sphingosine kinase (SK) 1, which in turn regulates diverse cellular signaling pathways.

Sphingosine analogue AAL-R increases TLR7-mediated dendritic cell responses via p38 and type I IFN signaling pathways.

Sphingosine analogues display immunosuppressive activities and thus have therapeutic potential in the treatment of autoimmune diseases. In this study, we investigated the effects of the sphingosine analogue AAL-R (FTY720 derivative) on dendritic cell (DC) response upon TLR stimulation. Unlike its known immunosuppressive activity, AAL-R increased TLR7-mediated DC responses by elevating the levels of MHC class I and costimulatory molecules and type I IFN expression and by enhancing the capacity of DCs to induce CD8(+) T cell proliferation.

Calcineurin-dependent negative regulation of CD94/NKG2A expression on naive CD8+ T cells.

Immune responses lead to expression of immunoregulatory molecules on T cells, including natural killer (NK) receptors, such as CD94/NKG2A on CD8(+) T cells; these receptors restrain CD8(+) responses, thereby preventing T-cell exhaustion in chronic infections and limiting immunopathology. Here, we examined the requirements for inducing CD94/NKG2A on T cells responding to antigen. In vitro, moderate induction of CD94/NKG2A expression occurred after exposure of naive CD8(+) (but not CD4(+)) cells to CD3 ligation or specific peptide.